CYP2D in the brain impacts oral hydrocodone analgesia in vivo.

Cytochrome P450 2D (CYP2D) metabolises many centrally-acting substrates including opioids. Hydrocodone, an opioid and CYP2D substrate, is metabolised to hydromorphone, an active metabolite. CYP2D in the brain is active in vivo and can alter drug response however, it is unknown whether metabolism by CYP2D in the brain alters oral hydrocodone induced analgesia. Propranolol, a selective CYP2D mechanism-based inhibitor, or vehicle, was administered into the right cerebral ventricle of male rats, (HAN Wistars, Envigo), 24 h before testing for analgesia from oral hydrocodone (or hydromorphone, a non-CYP2D substrate). Hydrocodone and its CYP2D-mediated metabolites were simultaneously quantified using a novel LC-MS/MS assay. After propranolol vs vehicle pretreatment, there was significantly higher analgesia from oral hydrocodone, and a significantly lower brain CYP2D metabolic ratio (an in vivo phenotype of brain CYP2D activity that was derived from the molar sum of hydromorphone and its metabolites divided by hydrocodone). The brain CYP2D metabolic ratio correlated significantly with analgesia. There was no pretreatment effect on plasma hydrocodone concentrations, elimination rates, or metabolic ratio (an in vivo phenotype for hepatic CYP2D activity). The liver CYP2D metabolic ratio did not correlate with analgesia. Propranolol pretreatment had no impact on analgesia from oral hydromorphone. These data suggest that inhibited CYP2D activity in brain, causing reduced metabolism of brain hydrocodone, resulted in higher analgesia from oral hydrocodone, despite hydrocodone having a lower µ-opioid receptor affinity than hydromorphone. Thus, variation in CYP2D in the brain may be an important source of interindividual differences in response to CYP2D substrates, including oral hydrocodone.

In silico drug repurposing against SARS-CoV-2 using an integrative transcriptomic profiling approach: Hydrocortisone and Benzhydrocodone as potential drug candidates against COVID-19.

COVID-19 pathogenesis is mainly attributed to dysregulated antiviral immune response, the prominent hallmark of COVID-19. As no established drugs are available against SARS-CoV-2 and developing new ones would be a big challenge, repurposing of existing drugs holds promise against COVID-19. Here, we used a signature-based strategy to delve into cellular responses to SARS-CoV-2 infection in order to identify potential host contributors in COVID-19 pathogenesis and to find repurposable drugs using in silico approaches. We scrutinized transcriptomic profile of various human alveolar cell sources infected with SARS-CoV-2 to determine up-regulated genes specific to COVID-19. Enrichment analysis revealed that the up-regulated genes were involved mainly in viral infectious disease, immune system, and signal transduction pathways. Analysis of protein-protein interaction network and COVID-19 molecular pathway resulted in identifying several anti-viral proteins as well as 11 host pro-viral proteins, ADAR, HBEGF, MMP9, USP18, JUN, FOS, IRF2, ICAM1, IFI35, CASP1, and STAT3. Finally, molecular docking of up-regulated proteins and all FDA-approved drugs revealed that both Hydrocortisone and Benzhydrocodone possess high binding affinity for all pro-viral proteins. The suggested repurposed drugs should be subject to complementary in vitro and in vivo experiments in order to be evaluated in detail prior to clinical studies in potential management of COVID-19.

Pre-exposure of adolescent mice to morphine results in stronger sensitization and reinstatement of conditioned place preference than pre-exposure to hydrocodone.

BACKGROUND: Opioids are commonly prescribed to treat moderate-to-severe pain. However, their use can trigger the development of opioid use disorder. A major problem in treating opioid use disorder remains the high rate of relapse. AIM: The purpose of this study was to determine whether there are differences among opioids in their ability to trigger relapse after pre-exposure during adolescence. METHODS: On postnatal day 33, mice were examined for the acute locomotor response to saline, morphine, or hydrocodone (5 mg/kg). They were administered with the corresponding opioid or saline during postnatal days 34-38 (20 mg/kg) and 40-44 (40 mg/kg). On postnatal day 45, they were recorded for the development of locomotor sensitization (5 mg/kg). Starting on postnatal day 55, mice were examined for the acquisition (1, 5, 10, 20, and 40 mg/kg), extinction, and drug-induced reinstatement (1, 2.5, and 5 mg/kg) of conditioned place preference. RESULTS: There were no significant differences in the acute locomotor response to morphine and hydrocodone. Morphine induced significantly stronger locomotor sensitization as compared to hydrocodone. Pre-exposure to morphine, but not hydrocodone, sensitized the acquisition of conditioned place preference. There were no significant differences in extinction rates. Mice pre-exposed to morphine reinstate conditioned place preference after priming with a 1 mg/kg dose. In contrast, higher priming doses were required for reinstatement in all other experimental groups. CONCLUSIONS: Adolescent mice administered with morphine develop greater sensitization to its effects and subsequently reinstate conditioned place preference more readily than mice administered with hydrocodone. This suggests higher risk for relapse after pre-exposure to morphine during adolescence as compared to hydrocodone.

Response to opioids is dependent on sociability levels.

Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.

Selective and Wash-Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single-Molecule Imaging of µ-Opioid Receptor Dimerization.

µ-Opioid receptors (µ-ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how µ-ORs produce specific effects in living cells. We developed new fluorescent ligands based on the µ-OR antagonist E-p-nitrocinnamoylamino-dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single-molecule imaging of µ-ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of µ-ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that µ-ORs interact with each other to form short-lived homodimers on the plasma membrane. This approach provides a new strategy to investigate µ-OR pharmacology at single-molecule level.

Lack of Influence by CYP3A4 and CYP3A5 Genotypes on Pain Relief by Hydrocodone in Postoperative Cesarean Section Pain Management.

BACKGROUND: Genetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief. METHOD: Blood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score. RESULTS: Two-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes. CONCLUSIONS: With respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2  = 0.4446], PK AQ [ρ2  = 0.5179], Tmax [ρ2  = 0.5093], and early systemic exposure [ρ2  = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in P rats.

Hydrocodone (HYD) is one of the most widely prescribed opioid analgesic drugs. Several neurotransmitters are involved in opioids relapse. Among these neurotransmitters, glutamate is suggested to be involved in opioid dependence and relapse. Glutamate is regulated by several glutamate transporters, including glutamate transporter 1 (GLT-1) and cystine/glutamate transporter (xCT). In this study, we investigated the effects of ceftriaxone (CEF) (200 mg/kg, i.p.), known to upregulate GLT-1 and xCT, on reinstatement to HYD (5 mg/kg, i.p.) using the conditioned place preference (CPP) paradigm in alcohol-preferring (P) rats. Animals were divided into three groups: 1) saline-saline group (SAL-SAL); 2) HYD-SAL group; and 3) HYD-CEF group. The CPP was conducted as follows: habituation phase, conditioning phase with HYD (i.p.) injections every other day for four sessions, extinction phase with CEF (i.p.) injections every other day for four sessions, and reinstatement phase with one priming dose of HYD. Time spent in the HYD-paired chamber after conditioning training was increased as compared to pre-conditioning. There was an increase in time spent in the HYD-paired chamber with one priming dose of HYD in the reinstatement test. HYD exposure downregulated xCT expression in the nucleus accumbens and hippocampus, but no effects were observed in the dorsomedial prefrontal cortex and amygdala. Importantly, CEF treatment attenuated the reinstatement effect of HYD and normalized xCT expression in the affected brain regions. These findings demonstrate that the attenuating effect of HYD reinstatement with CEF might be mediated through xCT.

Pain Treatment Practices of Community-Dwelling Black Older Adults.

Black older adults often experience disparities in pain treatment that results in unmet pain needs. The aims of this study were to assess the pain management experiences of a group of community dwelling Black older adults and identify gaps in clinical practice. A qualitative, descriptive design was employed using the methodology of ethnography. The setting was an urban, low-income, community elderly housing high-rise facility. Participants included facility residents (n = 106); of these, 20 completed structured qualitative interviews. The Brief Pain Inventory and qualitative interviews were used to determine pain prevalence, treatment practices, and barriers. Eighty-six percent of the participants had severe pain with a mean worst pain rating of 7 on a 0 to 10 scale. Pain interfered moderately with general activity (5.59), walking (5.73) and normal work (5.70), also measured on 0 to 10 scales. Participants preferred non-opioid analgesics, topical over-the-counter treatments, and nonpharmacological interventions such as prayer/meditation, and exercise for treatment. Medications most commonly used by participants for pain management included, hydrocodone with acetaminophen (28.6%), nonsteroidal anti-inflammatory drugs (13.2%), acetaminophen with codeine (12%), and tramadol (9.9). Qualitative interviews revealed that pain management barriers were centered around communication concerns about side effects, fears of addiction, and provider mistrust. A communication gap exists between patients and providers. Discussing patient treatment preferences, providing balanced treatment information, and following-up with patients on treatment plan effectiveness by phone can improve how pain is managed for Black older adults.

Reversal of oxycodone and hydrocodone tolerance by diazepam.

The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs.

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.

This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature.

Burn injury decreases the antinociceptive effects of opioids.

Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.

Gender difference in prescription opioid abuse: A focus on oxycodone and hydrocodone.

Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women's data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects.

Abuse liability assessment of hydrocodone under current draft regulatory guidelines.

INTRODUCTION: The abuse liability of hydrocodone was assessed in male Sprague-Dawley rats under the European Medicines Agency, the International Commission on Harmonisation, and the U.S. Food & Drug Administration draft guidelines for the non-clinical investigation of the dependence potential of medicinal products. METHODS: Self-administration, drug discrimination, and repeat-dose two week dependence liability studies were conducted to compare hydrocodone to the prototypical opiates, morphine and oxycodone. RESULTS: Hydrocodone was self-administered, produced an opiate-like subjective discriminative generalization profile and produced a significant discontinuation syndrome following abrupt treatment cessation that was quantitatively and qualitatively similar to morphine and/or oxycodone. CONCLUSION: Hydrocodone has abuse liability more similar to Schedule II opiates than other Schedule III compounds currently controlled under the U.S. Controlled Substance Act.

Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors.

Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system.

Hydrocodone extended-release: pharmacodynamics, pharmacokinetics and behavioral pharmacology of a controversy.

Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro(®), an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDA's Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to the Expert Panel's opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy.

Hydrocodone in postoperative personalized pain management: pro-drug or drug?

BACKGROUND: Genetic variations in enzymes that produce active metabolites from pro-drugs are well known. Such variability could account for some of the clinically observed differences in analgesia and side effects seen in postoperative patients. Using genotyping and quantitation of serum concentrations of hydrocodone and its metabolites, we sought to demonstrate the clinical effects of the metabolites of hydrocodone on pain relief. The objective of the current study was to determine whether CYP2D6 genotype and serum hydromorphone levels account for some of the variability in pain relief seen with hydrocodone in a cohort of women post-Cesarean section. METHODS: In 156 post-Cesarean section patients who received hydrocodone, we assessed serum opioid concentrations and CYP2D6 genotypes. Blood samples were collected at that time for genotyping and determination of concentrations of hydrocodone and metabolites by LC-MS/MS. Multivariate analysis was used to determine the relationship between CYP2D6 genotypes, pain relief, side effects, and serum concentrations of hydrocodone and hydromorphone. RESULTS: The CYP2D6 genotyping results indicated that 60% of subjects were extensive, 30% intermediate, 3% poor, and 7% ultra-rapid metabolizers. In the poor metabolizers, the mean plasma hydromorphone concentration was 8-fold lower when compared to that of ultra-rapid metabolizers. Hydromorphone, and not hydrocodone concentrations correlated with pain relief. CONCLUSIONS: This study shows that hydromorphone is generated at substantially different rates, dependent on CYP2D6 genotype. Pain relief correlated with plasma concentrations of hydromorphone, and not with hydrocodone. This suggests that pain relief will vary with CYP2D6 genotype. Inability to metabolize hydrocodone to hydromorphone as seen in the poor metabolizers should alert the clinician to consider alternative medications for managing pain postoperatively.

In vivo activity of norhydrocodone: an active metabolite of hydrocodone.

Hydrocodone is primarily metabolized to hydromorphone and norhydrocodone. Although hydromorphone is a known active metabolite of hydrocodone, the in vivo activity of norhydrocodone is not well documented. In the current study, the pharmacodynamics of norhydrocodone were evaluated and compared with hydrocodone and hydromorphone. Binding studies established that norhydrocodone, similar to hydrocodone and hydromorphone, is a µ-selective opioid ligand. In vivo analgesia studies (tail flick) demonstrated that, following subcutaneous, intrathecal, and intracerebroventricular administration, norhydrocodone produced analgesia. Following subcutaneous administration, norhydrocodone was ∼70-fold less potent, and hydromorphone was ∼5.4-fold more potent than hydrocodone in producing analgesia. Following intrathecal administration, norhydrocodone produced a shallow analgesia dose-response curve and maximal effect of 15-45%, whereas hydrocodone and hydromorphone produced dose-dependent analgesia. Intrathecal hydromorphone was ∼174-fold more potent than intrathecal hydrocodone. Following intracerebroventricular administration, norhydrocodone had similar potency to hydrocodone in producing analgesia, while hydromorphone was ∼96-fold more potent than hydrocodone. Analgesia induced by the three drugs following subcutaneous, intrathecal, and intracerebroventricular administration was antagonized by subcutaneous naltrexone, confirming that it is opioid receptor-mediated. Subcutaneous norhydrocodone-induced analgesia was completely blocked by intracerebroventricular naltrexone, indicating that norhydrocodone-induced analgesia is likely a supraspinal effect. Seizure activity was observed following intrathecal administration of all three drugs. Norhydrocodone and hydromorphone were ∼3.7 to 4.6-fold more potent than hydrocodone in inducing seizure activity. Naltrexone did not antagonize opioid-induced seizure activity, suggesting that seizures were not opioid receptor-mediated. Taken together, norhydrocodone is an active metabolite of hydrocodone and may contribute to therapeutic and toxic effects following hydrocodone administration.